Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: http://www.tandfonline.com/loi/irnf20

Association of interleukin 18-607A/C and -137C/

G polymorphisms with oxidative stress in renal
transplant recipients

Fatih Davran, Vural Taner Yilmaz, Bilge Karatoy Erdem, Meral Gultekin,
Gultekin Suleymanlar & Halide Akbas

To cite this article: Fatih Davran, Vural Taner Yilmaz, Bilge Karatoy Erdem, Meral Gultekin,
Gultekin Suleymanlar & Halide Akbas (2016) Association of interleukin 18-607A/C and -137C/G
polymorphisms with oxidative stress in renal transplant recipients, Renal Failure, 38:5, 717-722,
DOI: 10.3109/0886022X.2016.1158034

To link to this article: https://doi.org/10.3109/0886022X.2016.1158034

Published online: 16 Mar 2016.

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RENAL FAILURE, 2016
VOL. 38, NO. 5, 717–722
http://dx.doi.org/10.3109/0886022X.2016.1158034

CLINICAL STUDY

Association of interleukin 18-607A/C and -137C/G polymorphisms with

oxidative stress in renal transplant recipients
Fatih Davrana, Vural Taner Yilmazb, Bilge Karatoy Erdema, Meral Gultekinc, Gultekin Suleymanlarb and
Halide Akbasa
a
Department of Biochemistry, Faculty of Medicine, Akdeniz University, Antalya, Turkey; bDivision of Nephrology, Department of Internal
Medicine, Faculty of Medicine, Akdeniz University, Antalya, Turkey; cDepartment of Microbiology, Faculty of Medicine, Akdeniz
University, Antalya, Turkey

ABSTRACT ARTICLE HISTORY

Objectives IL-18 mediates various inflammatory and oxidative responses including renal injury, Received 5 October 2015
fibrosis, and graft rejection. It has been reported that the promoter -607 and -137 polymorphisms Revised 29 January 2016
of IL-18 influence the level of IL-18. This prospective observational study investigated the associ- Accepted 18 February 2016
ation between oxidative stress with IL-18-607 and -137 polymorphisms in renal transplant Published online 11 March
2016
recipients. Patients and methods This study included 75 renal transplant recipients (28 female,
47 male) from living-related donors. Blood samples were collected immediately before and after KEYWORDS
transplantation at day 7 and month 1. Serum IL-18, creatinine, cystatin C, CRP, and oxidative stress Interleukin-18 gene
markers (TOS, TAC) were measured. The Oxidative Stress Index (OSI) was calculated. polymorphisms; oxidative
Polymorphisms of the promoter region of the IL-18 gene, IL18-607A/C, and -137C/G were deter- stress; renal transplantation
mined by analysis of a ‘‘real-time PCR/Melting curve’’. Results Serum creatinine, cystatin C, CRP,
IL-18, TOS, and OSI levels significantly decreased after transplantation. Post-transplant levels of
serum TAC and estimated GFR demonstrated consistent significant increases. Serum IL-18 levels
were significantly higher in patients with IL-18-137 GG and IL-18-607 CC genotypes before trans-
plantation. Conclusion Our results indicate that the IL-18-137 GG and -607 CC genotypes contrib-
ute to higher IL-18 levels; however, the influence of these polymorphisms on oxidative stress has
not been observed.

Introduction factor-kappa B (NF-jB) and stimulating the subsequent

Interleukin (IL-18) is a macrophage-derived multifunc-
tional cytokine involved in both mediator and predictor
of acute renal injury; it mediates a wide range of inflam-
matory and oxidative responses including renal injury,
fibrosis, and graft rejection. IL-18 might be a ‘‘connect-
ing’’ molecule between inflammation and fibrosis. IL-18
plays a role in the development of oxidative stress; stud-
ies using inflammasome NLRP3/NALP3, known to induce
the expression of IL-18, demonstrated increased produc-
tion of reactive oxygen species.1 The NLRP3 inflamma-
some, one of the best characterized, controls the
activation of caspase-1. Following activation, cleaved
caspase-1 will cleave pro-IL-1b and pro-IL-18 into bio-
logically active pro-inflammatory cytokines – mature
IL-1b and mature IL-18, which are then released into the
extracellular environment.2
Oxidative stress, defined as an excess of pro-oxidant
status not balanced by an adequate antioxidant defense
system, can induce inflammation by activating nuclear
production of proinflammatory cytokines and chemo-
kines.3,4 Markers of oxidative stress, including elevated
levels of malondialdehyde (MDA) and reduced antioxi-
dant activity, have been reported in renal patients.5–9
The normalization of kidney function after transplant-
ation can improve oxidative stress10 but some reports
suggested that11,12 increased oxidative stress in renal
transplant recipients, particularly in the early phase13,14
and, thereafter, accompanied by chronic allograft dys-
function.11,15–18 Serum (or plasma) concentrations of dif-
ferent oxidant and antioxidant molecules can be
measured in laboratories separately; however, the meas-
urements are time-consuming, labor-intensive, costly,
and require complicated techniques. Since the measure-
ment of different oxidant/antioxidant molecules separ-
ately is not practical, the measurements of these
molecules as total oxidant status (TOS) and total antioxi-
dant capacity (TAC) are more applicable.19
It has been well recognized that the promoter poly-
morphisms of interleukin-18 (IL-18) influence the level

CONTACT Professor Halide Akbas, MD halideakbas@akdeniz.edu.tr Department of Biochemistry, Akdeniz University, Faculty of Medicine, Antalya,
Turkey
ß 2016 Taylor & Francis
718 F. DAVRAN ET AL.

Table 1. Demographic features of all patients and IL18–607/–137 gene polymorphism groups.
IL18-607 gene polymorphism IL18-137 gene polymorphism
Heterozygote
All patients Wild (CC) Mutant (AA) Heterozygote (CA) Wild (GG) Mutant (CC) (GC)
Numbers (%) 75 (100) 40 (53) 13 (17) 22 (30) 49 (65) 2 (3) 24 (32)
Recipient age (year) 38.2 6 13 38.1 6 14.2 40 6 14.2 37.5 6 10.1 36.3 6 12.6 33.5 6 0.7 42.5 6 13.6
Donor age (year) 47.2 6 12.2 47.4 6 12.4 45.9 6 10.8 47.8 6 13.1 47.9 6 11.8 53.5 6 4.9 45.4 6 13.5
Gender (F/M) (%) 28/47 (36/64) 14/26 (35/65) 7/6 (53/47) 7/15 (32/68) 18/31 (37/63) 1/1 (50/50) 9/15 (37/63)
BMI (kg/m2) 24.1 6 4.9 25 6 4.8 22.3 6 3.2 23.6 6 5.3 23.8 6 5 20 6 0.5 25.1 6 4.4
Types of renal replacement therapy
PD 5 (7%) 5 (13%) 0 0 5 (10%) 0 0
HD 31 (41%) 16 (40%) 5 (38%) 10 (45%) 21 (43%) 0 10 (41%)
Preemptive 39 (52%) 19 (47%) 8 (62%) 12 (55%) 23 (47%) 2 (100%) 14 (59%)
The etiologies of end stage renal disease
Hypertension 18 (24%) 8 (20%) 4 (31%) 6 (27%) 8 (16%) 0 10 (42%)
DM 8 (11%) 5 (13%) 1 (8%) 2 (9%) 6 (13%) 1 (50%) 1 (4)
Nephrolithiasis 11 (15%) 5 (13%) 2 (15%) 4 (18%) 8 (16%) 0 3 (13%)
GN 6 (8%) 1 (4%) 2 (15%) 3 (14%) 4 (8%) 0 2 (8%)
Unknown 25 (32%) 16 (40%) 4 (31%) 5 (23%) 18 (37%) 1 (50%) 6 (25%)
Other 7 (10%) 5 (10%) 0 2 (9%) 5 (10%) 0 2 (8%)
The number of HLA matches
0 9 (12%) 6 (16%) 1 (8%) 2 (9%) 7 (14%) 0 2 (8%)
1–5 60 (80%) 31 (76%) 11 (84%) 18 (82%) 38 (78%) 2 (100%) 20 (84%)
6 6 (8%) 3 (8%) 1 (8%) 2 (9%) 4 (8%) 0 2 (8%)
PD, peritoneal dialysis; HD, hemodialysis; DM, diabetes mellitus; GN, glomerulonephritis. Results are expressed as numbers and percentages.

of cytokine expression. Five different single nucleotide
polymorphic positions in the promoter region have
been identified: 656 G/T, 607 C/A, 137 G/C, þ113
T/G, and þ127 C/T; however, only two of them have
functional relevance; a change from C to A at position
607 (rs1946518) and a substitution at position 137
from G to C (rs187238). It has been reported that the
promoter -607 and -137 polymorphisms of IL-18 influ-
ence the level of cytokine IL-18 expression. Individuals
homozygous for the 607 C and 137 G express higher
levels of IL-18.20
There are limited data related with oxidative stress
and renal transplantation in the early stages. Therefore,
we investigated the time-dependent changes in the oxi-
dant/antioxidant balance during the first month after
transplantation by measuring the TOS and TAC. We also
determined the effect of IL-18 gene promoter polymor-
phisms on oxidative stress in renal transplant patients
and examined the relationship between these markers
and early graft function.
Materials and methods
Seventy-five living-donor kidney transplant recipients
who were at least 18 years old were recruited into the
study (28 female, 47 male; mean age: 38.28 6 13.03).
The study was conducted in accordance with the ethical
standards of our Institutional Ethics Committee and with
the Helsinki Declaration, and all patients provided writ-
ten informed consent. Patients were excluded who had
transplanted from a cadaveric donor, malignancy, com-
bined (pancreas or liver) transplantation, or graft failure
related to surgical causes. Demographic information
about patients such as age, sex, HLA compatibility, pri-
mary disease, and dialysis duration are presented in
Table 1.
As immunosuppressive treatment protocol, calci-
neurin inhibitors (Tacrolimus, an initial dose of 1.5 mg/
kg/day-two equal doses), mycophenolate mofetil
(2  1 g/d), monoclonal antibodies (basiliximab 20 mg, 0
and 4th day), mTOR inhibitors (Everolimus, 2  1 mg
starting dose in two equal doses) was used. Drug doses
were adjusted according to the target blood levels.
The blood samples were collected immediately
before and after surgery at day 7, month 1. The samples
were centrifuged at 4000 rpm for 5 min. The sera were
stored until analysis day at 80  C. Serum creatinine
and CRP measurements were performed by using ori-
ginal commercial kits in the Cobas 8000 auto analyzer
(Roche Diagnostics, Mannheim, Germany). The results
were expressed as mg/dL. Serum cystatin C levels were
measured by using the particle-enhanced immunone-
phelometric (PENIA) method in a BN II Nephelometer
(Siemens Healthcare Diagnostics Inc., Tarrytown, NY).
The results were given as mg/L. Serum IL-18 levels were
measured by Enzyme-Linked Immunosorbent Assay
(ELISA) method (eBioscience Human IL-18 Instant ELISA,
eBioscience Inc., San Diego, CA) (catalog no.
BMS267INST). The results are expressed as pg/mL.
Estimated glomerular filtration rates (eGFR) were calcu-
lated using the ‘‘Chronic Kidney Disease Epidemiology’’
(CKD-EPI) formula.21
Serum TAC levels were determined using an auto-
mated measurement method as previously described

by Erel.19 In the assay, ferrous ion solution, present in
reagent 1, was mixed with hydrogen peroxide, present
in reagent 2. The sequentially produced radicals, such as
brown-colored dianisidine radical cation produced by
the hydroxyl radical, are also potent radicals. Using this
method, the antioxidative effect of the sample on the
potent free radical reactions initiated by the produced
hydroxyl radical was determined. The results were
expressed as mmol Trolox Equiv/L.
Serum TOS levels were determined by using an auto-
mated measurement method developed by Erel.19
Oxidants present in the sample oxidize the ferrous
ion–o-dianisidine complex to ferric ion. The oxidation
reaction is enhanced by glycerol molecules, which are
abundantly present in the reaction medium. The ferric
ion makes a colored complex with xylenol orange in an
acidic medium. The color intensity, which can be meas-
ured spectrophotometrically, is related to the total
amount of oxidant molecules present in the sample. The
assay is calibrated with hydrogen peroxide, and the
results are expressed in terms of lmol H2O2 Equiv/L.
Oxidative stress index (OSI) values were calculated using
a TOS/TAC ratio. The results were given as arbitrary
units.
Genomic DNA extracts are obtained from peripheral
venous blood by using DNA Isolation Kit I (automatic
Isolation Kit) at Magna Pure LC instrument (Roche
Diagnostics, Mannheim, Germany) for IL-18 gene pro-
moter -607 A/C and -137 C/G polymorphism analysis.
Real-time PCR/melting curve genotyping analysis was
performed by using Roche Light Cycler 2.0 device
(Roche Diagnostics, Mannheim, Germany) with FRET
(Fluorescence Resonance Energy Transfer) hybridization
probes (TIB MOLBIOL, Berlin, Germany, catalog no. for
IL-18-137 SNP, for rs187238IL18 and IL-18-607 SNP;
rs1946518IL18). Polymerase chain reactions were per-
formed in a total reaction volume of 20 lL.
All statistical analyses were done with SPSS version
20.0 (SPSS Inc., Chicago, IL) and a significance level of
0.05 was considered. A Kolmogorov–Smirnov test was
performed to assess the deviation from a normal distri-
bution. Quantitative variables were summarized as
mean and standard deviation (SD), or as median.
Differences among all parameters at different time
points were assessed by ANOVA, Student t test, or
Mann–Whitney’s U test for quantitative variables. The
analysis of correlation was done by Spearman or
Pearson test.
Results
The Turkish transplant patient population consists
wholly of patients of Caucasian descent. General patient
RENAL FAILURE 719
Table 2. Frequency of alleles and genotypes of interleukin-18
gene promoter polymorphism in kidney recipients.
Parameters n %
IL-18-607 C Allele frequency 102 68
A Allele frequency 48 32
CC Genotype frequency 40 53
CA Genotype frequency 22 30
AA Genotype frequency 13 17
IL-18-137 G Allele frequency 122 81
C Allele frequency 28 19
GG Genotype frequency 49 65
GC Genotype frequency 24 32
CC Genotype frequency 2 3
characteristics and demographic features are shown in
Table 1. Genotypes for IL-18-607 promoter region poly-
morphism are defined as homozygous-Wild (CC), homo-
zygous-mutant (AA), and heterozygous (CA). Similarly
IL-18-137 promoter polymorphism is defined as homo-
zygous-Wild (GG), homozygous-mutant (CC), and het-
erozygous (GC). The distribution of alleles and
genotypes of the analyzed cytokine polymorphisms is
presented in Table 2. The frequency of the genotype
IL-18-607 CC was 53%, whereas 30% of patients were CA
and 17% of patients were AA. The frequency of the
genotype IL-18-137 GG was 65%, whereas 32% of
patients were GC and 3% of patients were CC.
Table 3 summarizes the serum creatinine, cystatin-C,
CRP, IL-18, TOS, TAC levels, OSI, and eGFR values in
patients before and after transplantation at day 7 and
month 1. Serum creatinine and cystatin C levels
decreased after transplantation, while eGFR values
increased. No significant differences were observed
between post-transplant day 7 and month 1 for these
parameters (Table 3). Serum IL-18 levels were signifi-
cantly decreased after transplantation. Serum CRP levels
were found to have significantly decreased at month 1.
Serum TOS levels and OSI values were significantly
higher before transplantation, while serum TAC levels
were found to be significantly lower (Figure 1). We did
not observe any significant differences between post-
transplant day 7 and month 1 for oxidative stress
parameters.
We observed significantly negative correlations
between TAC with TOS and OSI before transplantation
(respectively, r ¼ 0.729, r ¼ 0.938, p ¼ 0.001). A signifi-
cantly strong positive correlation was also found
between TOS and OSI in same period (r ¼ 0.878,
p ¼ 0.001). While we found significantly negative corre-
lations between TAC with TOS and OSI at day 7 after
transplantation (respectively, r ¼ 0.673, p ¼ 0.001,
r ¼ 0.706, p ¼ 0.010), a strong positive correlation was
found between TOS and OSI (r ¼ 0.978, p ¼ 0.001).
Similar findings were also observed at month 1 after
transplantation (for TAC vs. TOS and OSI; respectively,
720 F. DAVRAN ET AL.

Table 3. Serum creatinine, cystatin-C, CRP, IL-18, TAC, TOS levels, OSI, and eGFR values before and after
transplantation at day 7 and month 1. Data are given as mean 6 standard error.
Post-transplant Post-transplant
Parameters Pre-transplanta day 7b month 1c p Values
Creatinine (mg/dL) 8.18 6 2.83 1.30 6 0.39 1.32 6 0.41 1–2 5 0.001
1–3 5 0.001
2–3 ¼ 0.355
GFR-CKD-EPI (mL/dk/1.73m2) 7.77 6 3.02 69.03 6 21.98 68.80 6 24.00 1–2 5 0.001
1–3 5 0.001
2–3 ¼ 0.759
Cystatin-C (mg/L) 5.18 6 1.51 1.60 6 0.43 1.58 6 0.27 1–2 5 0.001
1–3 5 0.001
2–3 ¼ 0.558
CRP (mg/L) 0.43 6 0.20 0.54 6 0.23 0.13 6 0.09 1–2 ¼ NS
1–3 5 0.001
2–3 5 0.001
IL-18 (pg/mL) 228.46 6 110.70 197.65 6 85.53 202.51 6 86.78 1–2 5 0.001
1–3 5 0.026
2–3 ¼ 0.233
TAC (Trolox Equiv mmol/L) 0.43 6 0.09 0.45 6 0.06 0.46 6 0.05 1–2 5 0.006
1–3 5 0.006
2–3 ¼ 0.639
TOS (lmol H2O2 Equiv/L) 37.21 6 31.64 12.40 6 10.71 11.48 6 6.85 1–2 5 0.001
1–3 5 0.001
2–3 ¼ 0.132
OSI (AU) 5.72 6 1.77 2.48 6 1.40 2.36 6 1.10 1–2 5 0.001
1–3 5 0.001
2–3 ¼ 0.621
p Values of different periods are given in Table 2. p < 0.05 was accepted as significant and signed as bold. NS, not significant.
a
Pre-transplant.
b
Post-transplant day 7.
c
Post-transplant month 1.

r ¼ 0.512, p ¼ 0.001, r ¼ 0.613, p ¼ 0.001; for TOS and

OSI; r ¼ 0.969, p ¼ 0.001).
Patients with the IL-18-137 GG and IL-18-607 CC
genotype had significantly higher IL-18 serum levels
compared with other genotypes. Although we observed
significant differences in serum IL-18 levels according to
IL-18 607 and -137 polymorphisms, the influence of
these polymorphisms on oxidative stress parameters
have not been observed. Due to the low number of IL-
18-137 CC mutant patients (n ¼ 2), these data were not
include in the study.

Discussion
On one hand, dialysis therapies are able to improve the
metabolic status in patients with end-stage renal dis-
ease (ESRD). On the other hand, they have an ameliorat-
ing effect on inflammation and oxidative stress.
Regarding renal transplantation, the best option in the
renal replacement therapies is associated with signifi-
cantly improved long-term survival. Several theories
have been proposed for this survival advantage includ-
ing better clearance of uremic toxins, improvement of
cardiac capacity, and nutritional status. The normaliza-
tion of kidney function after transplantation can
improve oxidative stress, but some reports suggested
that increased oxidative stress in renal transplant
Figure 1. The oxidative stress parameters before and after
transplantation at day 7 and month 1. Data are given as
mean 6 standard error.
recipients, particularly in the early phase and thereafter,
accompanied by chronic allograft dysfunction.10–18,22
In this study, we investigated the time-dependent
changes in oxidative stress and inflammation with res-
toration of renal function by transplantation. Our results
demonstrate a rapid decrease in serum TOS, IL-18,
CRP levels, and OSI values after renal transplantation.

Serum TAC levels and eGFR values demonstrated con-
sistent increases after transplantation. We observed that
restoration of renal function by transplantation
improves the chronic inflammation and oxidative stress
associated with uremia. This improvement is a conse-
quence of reactive oxygen species (ROS) detoxification
by the renal tubular function.23,24 Studies show that
renal tubular epithel arranges the redox status of ultrafil-
trate in selective transport and metabolic functions. The
aldehyde dehydrogenase enzyme is highly active in the
renal cortex, and loss of this important renal detoxifying
mechanism is primarily the cause of ROS accumulation
in ESRD.10
Calcineurin inhibitors (cyclosporine and tacrolimus)
are the main group of drugs necessary to prevent graft
rejection, and it is possible that these therapies may
also increase inflammation and oxidative stress. It has
been recorded in some studies that cyclosporine causes
enhancement in production of reactive oxygen species
in kidney and heart transplant recipients. In another
study, the effects of calcineurin inhibitors on total oxi-
dant and antioxidant status were compared and no sig-
nificant differences were found.25 In our study, the
effect of different immunosuppressive drugs on serum
oxidant and antioxidant parameters was not assessed,
because all patients were on a therapy with tacrolimus.
We observed that oxidative stress significantly
decreased in our patients under tacrolimus therapy.
Oxidative stress is also involved as one of the most
important components of the ischemia–reperfusion (I/R)
process and renal injury in renal transplantation.26–28
When the kidney scavenging capacity is insufficient for
the balancing of oxidative stress, increased production
of ROS might trigger an inflammatory response within
the graft. These processes lead to tissue damage and
graft dysfunction. On one hand, Fonseca et al.5 reported
that MDA levels significantly decreased during the first
post-transplant week when TAS levels did not exhibit
any significant changes even though they classified the
patients according to delayed graft function. On the
other hand, we observed significant differences for TOS
and TAC levels before and after transplantation. In con-
trast to their findings, our study highlights that the total
antioxidant status enhanced while TOS levels decreased
with transplantation.
The nuclear factor E2 (NFE2)-related factor 2 (Nrf2)
protein that regulates the expression of antioxidants
protects against oxidative damage triggered by injury
and inflammation. Disruption of Nrf2 has been reported
to cause increased production of proinflammatory cyto-
kines, such as interleukin (IL)-1b, tumor necrosis factor
(TNF)-a, and IL-6 in experimental mouse models.
Williams et al.29 reported that the increased oxidative
RENAL FAILURE 721
stress correlated with increased IL-18 expression in mice
deficient in NFE2-Nrf 2. Recent studies have also demon-
strated that IL-18 levels are associated with the severity
of renal damage. It has been shown that the individual
cytokine polymorphisms play an important role in graft
function.20,30 Therefore, we investigated the time-
dependent changes in the oxidant and the antioxidant
balance during the first month after transplantation and
examined the effect of IL-18 gene promoter polymor-
phisms on oxidative stress. We observed significant dif-
ferences in serum IL-18 levels according to IL-18-607
and -137 polymorphisms. Despite improved kidney
function and lower inflammatory and oxidative stress
biomarkers in the early post transplant period, the influ-
ence of IL-18-607 and -137 polymorphisms on these
markers have not been observed.
Although the results presented in our study are inter-
esting, some potential limitations should be considered.
Due to the limited number of patient, differences of IL-
18 gene polymorphisms in various populations, and
lengthy monitoring needs of patients, additional larger
studies are required to further confirm the association
of cytokine gene polymorphisms with oxidative stress.
Disclosure statement
The authors report that they have no conflicts of inter-
est. Funding information
In this study, Akdeniz University Scientific Research
Management Unit is supported by 2012.04.0103.003
with Project No.
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